Malignancy rates in thyroid nodules: a long-term cohort study of 17,592 patients

Objectives Ultrasound diagnosis of thyroid nodules has greatly increased their detection rate. Their risk for malignancy is estimated between 7 and 15% in data from specialized centers which are used for guidelines recommendations. This high rate causes considerable anxiety to patients upon first diagnosis. Here, we retrospectively analyzed the malignancy rate of sonographically diagnosed nodules larger than 1 cm from a primary/secondary care center when long-term longitudinal follow-up was included. Patients/methods In the study, 17,592 patients were diagnosed with a thyroid nodule larger than 1 cm, of whom 7776 were assessed by fine-needle aspiration cytology (FNAC) and 9816 by sonography alone. 9568 patients were initially discharged due to innocent results of FNAC and/or ultrasound. In 1904 patients, definitive histology was obtained, and 6731 cases were included in the long-term follow-up (up to 23 years, median 5 years). Results Malignancy was histologically confirmed in 189 patients (1.1% of all) when excluding accidentally diagnosed papillary microcarcinomas. 155 were diagnosed during the first year of management, 25 in years 2–5 of follow-up, 9 in years 6–10 and nil in 1165 patients followed beyond 10 years. Conclusions The malignancy rate of thyroid nodules from primary/secondary care was much lower than that previously reported. During follow-up for more than 5 years, their rate rapidly dropped to less than 1/1000 cases. This low malignancy rate may help to reassure patients first confronted with the diagnosis of a thyroid nodule, substantially reduce their anxiety and avoid unwarranted diagnostic and therapeutic procedures.

introduction of the Bethesda system for reporting thyroid cytopathology (TBSRTC) (1) were retrospectively reassigned to Bethesda classes (BC) 1-6. 790 patients underwent histological verification during initial year of management (IYM).
3,092 patients were followed longitudinally with a median follow-up of 5 year, of whom 403 were operated during follow-up (see Fig.1 of main paper).

FNAC-results
PPV and NPV of initial FNAC results were calculated for each Bethesda class (BC). PPV was calculated for all malignancies, using the definition: true positive/true positives plus false positive results, and NPV was defined by true negative/true negative plus false negative results. For calculation of NPV we combined 1,193 operated patients and the subgroup of 1,841 unoperated patients with follow-up over more than 3 years (median follow-up 7 years) to calculate true negative results.

Supplementary results and discussion
Distribution of FNAC-results and correlation of Bethesda classes with histology (see supplementary Table 1): Histologic verification was sought in 900 patients following a single FNAC and in another 293 after repeated procedures.
Out of additional 23 patients with a mptc the carcinoma was localized within the index nodule in 10 and outside in 13 patients, none of all patients with mptc showed lymph node involvement.
Our results for PPV and NPV of each BC fit well with those recently published by Sauter et al. (2) and Ng et al. (3), who also published follow-up data of their patients (see supplementary Table 2), Like them, we classified all nodule(s) of a patient who developed no sign of malignancy after a follow-up of longer than 3 years as truly benign and included them in the calculation of NPV.
Our data are qualitatively comparable to other seminal studies previously published (2)(3)(4)(5)(6)(7)(8)(9)(10)(11) (see supplementary Table 3) but show some distinct quantitative differences, including a relatively low percentage of patients classified as BC3. This Bethesda class has recently been the subject of controversial debate, particularly as it is only moderately reproducible (2,12). The fact that our results had to be reclassified according to the Bethesda system, which was introduced years after the start of our data collection (1), could be another factor underlying the divergence of our results from those of similar studies.
The percentage of BC5 and BC6 cases was also lower in our cohort than previously reported (see supplementary Table 3). This may be due to the origin of our cohort in primary/secondary care where one would expect a lower rate of malignancy than in findings from referral centers for thyroid cancer (see discussion of main paper). In addition, due to the much lower quality of the ultrasound equipment initially used, we performed FNAC in a large number of patients as a safety measure to clarify the dignity of a nodule. This increased the number of nodules with benign cytology and reduced the relative percentage of malignant findings.
Altogether, initial cytology revealed a benign result in 5,839 cases (75.1% of all initial FNAC`s classified as BC 2). Of these patients, 550 were sent for surgery without further FNAC during IYM, predominantly for diagnosis of a multinodular goiter but also where there was a high suspicion of malignancy (5 histologically diagnosed as PTC, and 2 as FTC). The ROM of all our BC2 patients (5,839 patients) calculated as 0.5% (see eTable 1) or 1.3% respectively when we restricted the analysis to those 2,202 patients treated by surgery or followed for more than 3 years (see supplementary Table 2)). This agrees well with the small number of larger, closely controlled studies conducted previously (2)(3)(4)7,(9)(10)(11) (see   supplementary Table 4).
Patients classified as BC1 pose a difficult diagnostic problem. They are composed of cases with non-diagnostic results but have, by definition, plain cysts where cyst fluids and virtually acellular specimens have been aspirated (1). In total, we diagnosed BC1 in 21.1 % of all FNACs but this percentage dropped to 8.2 % when we excluded the large number of pure thyroid cysts without solid components. In 1,004 patients (12.9%) pure cysts were diagnosed and aspirates sent for subsequent cytology. Surgery was performed in 120 patients (1 cystic PTC, 1 FTC, 1 MTC). Our results confirm previous findings of a low ROM of plain cysts and, as no malignancies were detected during long-term follow-up, they support the recent critical discussion on their inclusion to BC1 (13).
In 633 patients a nondiagnostic (non-cystic) BC1 result was found (8.1% of all patients with initial FNAC`s). 70 patients were sent for surgery (without an additional FNAC on account of suspicious ultrasound) confirming a malignancy in 9 cases (7 PTCs and 2 MTCs); 5 malignancies (3 PTCs, 1 FTC and 1 lymphoma) were diagnosed after repetition of FNAC.
Histological clarification is advisable in BC3+4 cases and mandatory in all BC5+6 cases.
Histology confirmed a malignancy in 5 of 26 BC3 patients (19%) and in 29 of 185 BC4 patients (16%), which fits well to previously published ROMs (see supplementary Table 4). In 5 18 of 27 patients classified as BC5 (67 %) a malignancy was histologically verified (3 patients of this group were lost to follow-up) and a malignancy was histologically confirmed in all 62 patients preoperatively classified as BC6, including the 10 patients with metastases (5 from lung cancer, 4 from a renal carcinoma and 1 from breast cancer).